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Is Chromogranin a Prohormone? Had Only a Fraction of the Pancreastatin Potency of the Peptide Characterized by Lee E

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Is Chromogranin a Prohormone? Had Only a Fraction of the Pancreastatin Potency of the Peptide Characterized by Lee E ~N...:.AT.;:...U=--R.;:...E_V_O_L_.~32_5 _22_J_A_NU_A_R_Y_l_98_7 _________ NEWS ANDVIEWS-------------------'--301 Peptide function small percentage of plasma chromogranin was processed to a pancreastatin-like molecule, or if native chromogranin A Is chromogranin a prohormone? had only a fraction of the pancreastatin potency of the peptide characterized by Lee E. Eiden Tatemoto et at .. It is clearly necessary to establish that the molecule isolated by IN THE 4 December issue of Nature!, K. terminal processing signal for the forma- Tatemoto et at. is indeed the substance Tatemoto and co-workers report the tion of pancreastatin from a chromogranin found at beta-cell and D-cell receptors in sequence of a newly discovered putative A-like precursor in the rat. vivo. It will be of special interest to deter- hormone, pancreastatin, which as its There is chromogranin, as well as mine if amidation is necessary for bio­ name implies inhibits insulin (and soma­ pancreastatin, immunoreactivity in the logical activity, because amidation of tostatin) secretion from the endocrine pancreas of several species, and both poly- other biologically active peptides such as pancreas. There is a striking structural peptides are present in the brain"!', consis- enkephalins seems to oc-cur differentially similarity between pancreastatin and part tent with a precursor-product relationship in central and autonomic nervous tissue, of bovine chromogranin A, whose se­ between chromogranin A and pancreas- and this differential post-translational quence was recently reported in Nature by tatin. Whether or not pancreastatin is gen- modification may be relevant to different, myself and collaborators, and independ­ erated from chromogranin A or a chromo- as yet undiscovered hormonal functions of ently in the EMBO Journal by Benedum granin A-like precursor must await the these molecules. In addition, there is pre­ et at. J. This similarity suggests that chromo­ sequencing of the porcine chromogranin cedent for cleavage at single basic amino­ granin A is a prohormone precursor for A complementary DNA, now under way, acid residues within the precursors of pancreastatin or a pancreastatin-like pep­ or the demonstration of the analogous other biologically active secretory pep­ tide. If so, Tatemoto and co-workers will pancreastatin in the bovine pancreas. tides" and thus pancreastatin residues have contributed decisively to the elucida­ GWPQ--AP--AMDGAGKTGAEEAQPPEGKGAREHSRQEEEEETAGAPQGLFRG tion of a least one of the physiological KETQRAAPGWPEDGAGKMGAEEAKPPEGKGEWAHSRQEEEE-MARAPQVLFRGGK functions of chromogranin A. Its role has * ** ***** ***** ****** ******** * ***#**** eluded neuroendocrinologists since its Top sequence, porcine pancreastatin; bottom sequence, bovine chromogranin A 243-296 (pre­ discovery 20 years ago4-7. chromogranin A 261-314)2. Single-letter code for amino acids. Stars, identical residues; dashes, Chromogranin A is the chief represen­ gaps introduced into either sequence to maximize alignment; hash, conservative substitution. tative of a family of acidic glycoproteins Alternatively, the pancreastatin-like I 1-49, 14-49,27-49,31-49 and 36-49 (or that are abundant throughout the peptide potentially encoded by chromog- chromogranin A 244-294, 248-294, 260- neuroendocrine system8--11. Chromogranin ranin A and pancreastatin itself could be 294, 267-294, 272-294, 279-294 and even A is about 10 per cent of the protein related members of a larger, hitherto un- 287-294) could be the actual biologically weight of catecholamine-secreting identified family of peptide hormones active peptide(s) produced by and se­ chromaffin cells of the adrenal medulla analogous to the secretin 'superfamily' of creted from any endocrine tissue. l3 3 and is found, often with related proteins gut hormones • Benedum et at. have In any event, the demonstration of bio­ variously called chromogranins Band C characterized a second bovine adreno- logical activity for a chromogranin A-deri­ and secretogranins I and II (ref. 12), in the medullary messenger RNA encoding a ved molecule would be a partial reward brain, pituitary, retina, thymus, parathy­ chromogranin A identical in size and with for the considerable efforts so far made to roid, sympathetic nervous system, enteric 98 per cent of the peptide and 94 per cent characterize and understand this ubiquitous nervous system, endocrine gut and endo­ of the nucleic acid sequences identical to but puzzling molecule. Further infonnation crine pancreas8--11. It is from the last-named the chromogranin messenger RNA char- validating or disproving a biosynthetic tissue that Tatemoto et at. isolated the 49- acterized by us'. Eberwine et al.14 report and/or genetic relationship between amino acid 'pancreastatin' whose struc­ that sequences hybridizing to a pancreastatin and chromogranin A, and ture and biological activity, together with pancreastatin-complementary oligonuc- linking chromogranin A to other endocrine 2 J the recently determined structure • of leoti de probe may be found in as many as functions, should accrue quickly. chromogranin A, may finally give a clue to five separate genes in the rat. These obser- Two of the authors of ref. 3 indepen­ the function of chromogranin A. vations suggest that chromogranin A and dently report the sequence similarity be­ Pancreastatin, a potent inhibitor of in­ pancreastatin are members of a peptide tween chromo gran in A and pancreastatin sulin secretion from the isolated rat pan­ hormone superfamily. For the moment, on page 305 of this issue!". D creas, is quite similar to residues 243-294 both possibilities seem equally likely. 1. Tatemoto. K. elal. Nalure 324, 476 (1986). of bovine chromogranin A (residues 261- Structural analysis of porcine chromogra- 2. [acangelo. A. elal. Nature 323, 82 (1986) . A b . .. d d 3 Benedum,U.M.elal.EMBOJ.5,1495(1986). 312 of prechromo gran in A): 71 per cent of nm or ovme pancreastatm IS nee e 4: Banks. P. & Helle. K. Riochem. J. 57, 40C (1965). the amino-acid residues of the two pep­ to distinguish between them. 5. Kirshner, N. elai. Science 154, 529 (1966). S I dd't' 1ft b 6. B1ashko,H.elal. Nalure2lS, 58 (1967). tides are identical (see figure). The simi­ evera a I iOna ques iOns mus e 7. Smith, A.D. & Winkler. H. Biochem. J. 103,483 (1967). larity is even greater (80 per cent, with one answered to clarify the relationship be- 8. O'Connor, D. T. Regulat. Peplides 6, 263 (1983). gap) in the carboxy-terminal 41 amino tween pancreastatin and chromogranin A. 9. Cohn, D.V., Elting, J.J. Frick, M. & Elde. R. Endocrinol- ogy 114, 1963 (1984). acids of pancreastatin. This is significant Does chromogranin A indeed generate a 10. Angeletti, R.H. Lab. Invesl. 55,387 (1986). in that all the biological activity of paD­ pancreastatin-like peptide in adrenal II. Winkler, H., Apps, D.K. & Fischcr-Colbric. R. Neurosci­ ence 18, 261 (1986). creastatin seems to be localized in the medulla, endocrine pancreas or any other 12. Cohn, D.V. ela/. Neuroscience (in the press). carboxy-terminal 17 amino acids of the tissue? Is native unprocessed chromogra- 13. Tatemoto, K. & Mutt, V. Proc. natn. Acad. Sci. U.S.A. 78, . A' If . ? Th 6603 (1981). peptide!. The next six nucleotides of nm Itse a pancreastatm. ese ques- 14. Eherwine, J. ef al. NeuYO.,ci Soc. Abstr. 12,568 (1986). bovine chromogranin A messenger RNA tions are crucial because the ubiquity of 15. Valentino, K.L. etal. Neurosci. Suc. Abslr. 12,569 (1986). encode the dipeptide Gly-Lys, a poten­ chromogranin A in the neuroendocrine 16. O'Connor, D.T. Hypertension 7,176 (1985). 17. Loh, Y,P. & Gainer, H. in Brain Peptide.\' (cds Krieger, tial processing signal for proteolytic cleav­ system would suggest that the role of D.T. Brownstein, M.J. & Martin, J.B.) 79 (Wiley, New age and carboxy-terminal amidation, con­ pancreastatin or pancreastatin-like mole- York,1983). sistent with the isolation of pancreastatin cules is not limited to the pancreas. In fact 18. Huttner. W. B & Bencdum, U. M. Nalure325, 305 (1987). as an amidated species. At the amino plasma levels of chromogranin A are suf- Lee E. Eiden is in the Unit on Molecular and terminus, chromogranin A contains a ficiently high!6 (about 3 nM) to stimulate Cellular Neurobiology, Laboratory o/Cell Bio­ lysine residue, which may be the amino- pancreastatin receptors even if only a logy, NIMH, Bethesda, Maryland 20892, USA. .
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